MX2 restricts HIV-1 and herpes simplex virus-1 by forming cytoplasmic biomolecular condensates that mimic nuclear pore complexes

Abstract

AbstractHuman myxovirus resistance 2 (MX2) can potently restrict HIV-1 and herpesviruses at a post-entry step by a process that requires MX2 interaction with the capsids of these viruses. The involvement of other host cell factors in this process, however, remains poorly understood. Here, we mapped the proximity interactome of MX2 revealing strong enrichment of phenylalanine-glycine (FG)-rich proteins related to the nuclear pore complex as well as proteins that are part of cytoplasmic ribonucleoprotein granules. MX2 interacts with these proteins to form multiprotein cytoplasmic biomolecular condensates that are essential for its anti-HIV-1 and -herpes simplex virus-1 (HSV-1) activity. MX2 condensate formation requires the disordered N-terminal region of MX2 and its dimerization. We also demonstrate that incoming HIV-1 and HSV-1 capsids associate with MX2 at dynamic cytoplasmic biomolecular condensates. Our results reveal that MX2 forms nuclear pore-mimicking cytoplasmic condensates that act as nuclear pore decoys, thereby interfering with nuclear entry of HIV-1 and HSV-1.